Retrospective analyses of three randomized, double-blind studies of desipramine in cocaine abuse treatment disclose that high desipramine plasma concentrations (greater than 200 ng./ml. at steady state) are associated with very poor pharmacotherapy outcome. These intriguing, retrospective, preliminary data are limited by small sample size and absence of an a priori focus on plasma concentrations. They are as yet insufficient to guide clinical care or provide certainty that a ceiling exists. If a ceiling is confirmed, the existing data alone cannot establish why it appears only in this disorder and not depression, or determine how strongly correct desipramine plasma concentrations contribute to its clinical effectiveness in cocaine abusers. We propose the first prospective evaluation of a possible ceiling of desipramine hydrochloride plasma concentration in cocaine abuse treatment. One hundred and twenty (120) DSM-lIlR cocaine dependent individuals will be randomly assigned to placebo (n=4O) or to desipramine (n=8O). A fixed dose of (3.0 mg./kg.) will be used to attempt to distribute the desipramine subjects into two equally sized groups above and below a preliminary estimate of 200 mg./ml. for the ceiling. The placebo condition is being used to 1) assess whether supra-ceiling plasma concentrations worsen outcome below placebo, as early observers suggest, and to 2) extend the number of randomized, controlled double-blind efficacy assessments in the controversial arena of desipramine for cocaine abuse treatment. Fixed dosage multi-week trials are needed to establish whether both 1) the retrospective observations reported in this application can be replicated in a prospective study, and 2) whether the relationship of plasma concentrations in later treatment weeks is similar to that presented for the earliest weeks of treatment, because the retrospective reports herein focus mainly on desipramine concentrations in the initial month of pharmacotherapy.